My long-term goal is to become an independently-funded academic clinician-scientist, performing translational research to improve outcomes for women with gynecologic malignancies. As an MD/PhD, I have laboratory experience in molecular and cellular biology using human gynecologic cancer cell lines in vitro. I seek a K23 Mentored Patient-Oriented Research Career Development Award to expand my skills in translational clinical trials and obtain a Masters of Science degree in Clinical Research (MSCR). This multi- disciplinary K23 proposal uses established cancer cell lines and primary cultures from endometrial tumors, gene expression profiling, and a clinical trial, to assess metformin as a drug for endometrial cancer therapy. Endometrial cancer is the fourth most common cancer among women in the United States, and the death rate from this disease has increased by 227% over the past ten years. Obesity and diabetes are linked to higher recurrence rates and death in the common form of endometrial cancer (type I, or endometriod). I hypothesize that metformin will act as an mTOR inhibitor and be an effective chemotherapeutic agent for a disease so impacted by obesity and insulin resistance. To understand metformin's anti-tumorigenic potential, I will assess the effects of metformin on proliferation, apoptosis and expression of key targets of metformin cell signaling in four endometrial cancer cell lines and in primary cultures of human endometrial cancer cells. In parallel, I will evaluate the biology of endometrial cancer in obese and non-obese women through gene expression profiling to identify appropriate targeted therapies to pair with metformin, and I will assess synergy between these agents and metformin in vitro. Lastly, I will determine the effect of metformin on the endometrium of obese and diabetic women with endometrial cancer by comparing each patient's endometrial biopsy with their hysterectomy specimen following 2-4 weeks of treatment with metformin. The effect of metformin on proliferation, apoptosis and downstream signaling pathways will be explored in tissue specimens and correlated to our findings with cultured endometrial cancer cells in vitro. Therapy during this preoperative window allows us to evaluate safely the biologic effect of metformin on human endometrial cancer in vivo. The training, curriculum, mentoring and 75% protected research time provided by the K23 award will enable me to establish myself as a translational researcher and clinical trialist. Through the K23 award, I will acquire the skills and a body of work to compete successfully for peer-reviewed grant support and ultimately, my first R01. My overall hope is to see the results of my bench science lead to clinical trials and the development of therapies that have a significant impact on the lives of women battling gynecologic cancers.